Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease

TLDR

Cardiac fibroblasts are the largest myocardial cell population, producing extracellular matrix proteins and cytokines, and their hyperactivity leads to fibrosis that impairs cardiac structure and function. This review aims to examine cardiac fibroblast roles in extracellular matrix formation, homeostasis, and remodeling across various heart diseases in patients and animal models. The authors synthesize findings from experimental animal models and genetically modified mice with altered expression of ECM regulatory proteins, MMPs, and TIMPs to elucidate fibroblast‑mediated remodeling mechanisms.

Abstract

Abstract Fibroblasts comprise the largest cell population in the myocardium. In heart disease, the number of fibroblasts is increased either by replication of the resident myocardial fibroblasts, migration and transformation of circulating bone marrow cells, or by transformation of endothelial/epithelial cells into fibroblasts and myofibroblasts. The primary function of fibroblasts is to produce structural proteins that comprise the extracellular matrix (ECM). This can be a constructive process; however, hyperactivity of cardiac fibroblasts can result in excess production and deposition of ECM proteins in the myocardium, known as fibrosis, with adverse effects on cardiac structure and function. In addition to being the primary source of ECM proteins, fibroblasts produce a number of cytokines, peptides, and enzymes among which matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), directly impact the ECM turnover and homeostasis. Function of fibroblasts can also in turn be regulated by MMPs and TIMPs. In this review article, we will focus on the function of cardiac fibroblasts in the context of ECM formation, homeostasis and remodeling in the heart. We will discuss the origins and multiple roles of cardiac fibroblasts in myocardial remodeling in different types of heart disease in patients and in animal models. We will further provide an overview of what we have learned from experimental animal models and genetically modified mice with altered expression of ECM regulatory proteins, MMPs and TIMPs.